Project Summary: Early life psychosocial adversity and stress are well-established as the most powerful environmental risk factors for poor neurodevelopmental and mental health outcomes in children. Impairments in developing emotion regulation and cognitive control and associated alterations in brain development have been shown to mediate the effects of adversity on risk for the development of psychopathology. Early psychosocial adversity impacts the epigenetic and inflammation-mediated processes that contribute to these negative outcomes, a process known as ?biological embedding of stress.? While this risk trajectory has been clearly linked to increased rates of psychopathology, the mechanisms of this process, its targetable mediators and how early in development they operate are yet to be determined. Here we focus on the effects of early life adversity on brain, emotion regulation and cognitive control outcomes relevant to risk for mental disorders, beginning antenatally and extending to age 3. We will examine the role of pre- and postnatal adversity/stress, the maternal and child perinatal gut microbiome and early caregiver support on these key neurodevelopmental outcomes utilizing state-of-the-art neuroimaging. Our unifying hypothesis is that these factors modulate systemic inflammatory responses, induce neuronal effects through this and other processes that adversely impact brain development in limbic and cortical regions, and mediate the effects of early adversity on child emotion regulation, cognitive control and mental health outcomes. These factors will be studied in a unique, prospectively ascertained cohort of 370 mothers and their offspring at high psychosocial risk being recruited as part of an already funded March of Dimes project at Washington University. The cohort will include both term- and prematurely-born infants and toddlers given the increased risk of psychosocial adversity and aberrant gut microbiome in preterm children. The offspring will be intensively prospectively studied from the 1st trimester to age 3, providing a unique dataset in which to examine the interrelationships among pre- and postnatal adversity, biomarkers of inflammation, the gut microbiome and developmental and mental health outcomes. The perinatal and early childhood periods are critical times to study these exposures as adverse neurodevelopment associated with adversity begins in utero through fetal programming. Likewise, the perinatal period is a critical developmental window for microbial influences, when gut microbial colonization has its most enduring effects. The proposed study merges established research groups in these areas in a center with advanced infant and childhood neuroimaging and extensive microbiome expertise, and offers an unprecedented opportunity to understand the mechanisms of the biological embedding of adversity on brain, cognitive and emotional trajectories in a high-risk cohort. We will also apply innovative computational methods, using Deep Learning, to extend understanding of these data. Findings will provide critical and novel insights to inform early preventive interventions relevant to emotional, cognitive and mental health outcomes for children at greatest risk.